Furosemide versus placebo for fluid overload in intensive care patients-The randomised GODIF trial second version: Statistical analysis plan.

BACKGROUND: Fluid overload is associated with increased mortality in intensive care unit (ICU) patients. The GODIF trial aims to assess the benefits and harms of fluid removal with furosemide versus placebo in stable adult patients with moderate to severe fluid overload in the ICU. This article describes the detailed statistical analysis plan for the primary results of the second version of the GODIF trial. METHODS: The GODIF trial is an international, multi-centre, randomised, stratified, blinded, parallel-group, pragmatic clinical trial, allocating 1000 adult ICU patients with moderate to severe fluid overload 1:1 to furosemide versus placebo. The primary outcome is days alive and out of hospital within 90 days post-randomisation. With a power of 90% and an alpha level of 5%, we may reject or detect an improvement of 8%. The primary analyses of all outcomes will be performed in the intention-to-treat population. For the primary outcome, the Kryger Jensen and Lange method will be used to compare the two treatment groups adjusted for stratification variables supplemented with sensitivity analyses in the per-protocol population and with further adjustments for prognostic variables. Secondary outcomes will be analysed with multiple linear regressions, logistic regressions or the Kryger Jensen and Lange method as suitable with adjustment for stratification variables. CONCLUSION: The GODIF trial data will increase the certainty about the effects of fluid removal using furosemide in adult ICU patients with fluid overload. TRIAL REGISTRATIONS: EudraCT identifier: 2019-004292-40 and ClinicalTrials.org: NCT04180397.

Bioimpedance and Duration of Organ Dysfunction in Septic Shock-A Prospective Observational Study.

Rationale: Bioimpedance may be a useful tool to guide fluid treatment and avoid organ dysfunction related to fluid overload. Objective: We examined the correlation between bioimpedance and organ dysfunction in patients with septic shock. Methods: Prospective observational study of adult intensive care unit patients fulfilling the sepsis-3 criteria. Bioimpedance was measured using a body composition monitor (BCM) and BioScan Touch i8 (MBS). We measured impedance at inclusion and after 24 h and reported the impedance, change in impedance, bioimpedance-derived fluid balance, and changes in bioimpedance-derived fluid balance. Organ markers on respiratory, circulatory, and kidney function and overall disease severity were ascertained on days 1-7. The effect of bioimpedance on the change in organ function was assessed by mixed effects linear models. We considered P < .01 as significant. Measurements and Main Results: Forty-nine patients were included. None of the single baseline measurements or derived fluid balances were associated with the course of organ dysfunction. Changes in impedance were associated with the course of overall disease severity (P < .001; with MBS), and with changes in noradrenaline dose (P < .001; with MBS) and fluid balance (P < .001; with BCM). The changes in bioimpedance-derived fluid balance were associated with changes in noradrenaline dose (P < .001; with BCM), cumulative fluid balances (P < .001; with MBS), and lactate concentrations (P < .001; with BCM). Conclusions: Changes in bioimpedance were correlated with the duration of overall organ failure, circulatory failure, and fluid status. Single measurements of bioimpedance were not associated with any changes in organ dysfunction.

Mild induced hypothermia and coagulation and platelet function in patients with septic shock: Secondary outcome of a randomized trial.

Coagulation abnormalities and microthrombi contribute to septic shock, but the impact of body temperature regulation on coagulation in patients with sepsis is unknown. We tested the hypothesis that mild induced hypothermia reduces coagulation and platelet aggregation in patients with septic shock. Secondary analysis of randomized controlled trial. Adult patients with septic shock who required mechanical ventilation from eight intensive care units in Denmark were randomly assigned to mild induced hypothermia for 24 h or routine thermal management. Viscoelastography and platelet aggregation were assessed at trial inclusion, after 12 h of thermal management, and 24 h after inclusion. A total of 326 patients were randomized to mild induced hypothermia (n = 163) or routine thermal management (n = 163). Mild induced hypothermia slightly prolonged activated partial thromboplastin time and thrombus initiation time (R time 8.0 min [interquartile range, IQR 6.6-11.1] vs. 7.2 min [IQR 5.8-9.2]; p = .004) and marginally inhibited thrombus propagation (angle 68° [IQR 59-73] vs. 71° [IQR 63-75]; p = .014). The effect was also present after 24 h. Clot strength remained unaffected (MA 71 mm [IQR 66-76] with mild induced hypothermia vs. 72 mm (65-77) with routine thermal management, p = .9). The proportion of patients with hyperfibrinolysis was not affected (0.7% vs. 3.3%; p = .19), but the proportion of patients with no fibrinolysis was high in the mild hypothermia group (8.8% vs. 40.4%; p < .001). The mild induced hypothermia group had lower platelet aggregation: ASPI 85U (IQR 50-113) versus 109U (IQR 74-148, p < .001), ADP 61U (IQR 40-83) versus 79 U (IQR 54-101, p < .001), TRAP 108 (IQR 83-154) versus 119 (IQR 94-146, p = .042) and COL 50U (IQR 34-66) versus 67U (IQR 46-92, p < .001). In patients with septic shock, mild induced hypothermia slightly impaired clot initiation, but did not change clot strength. Platelet aggregation was slightly impaired. The effect of mild induced hypothermia on viscoelastography and platelet aggregation was however not in a range that would have clinical implications. We did observe a substantial reduction in fibrinolysis.

Novel subgroups in acute respiratory failure based on the trajectories of three endotheliopathy biomarkers: A cohort study.

Baseline levels of endotheliopathy are associated with worse respiratory outcomes and mortality in undifferentiated acute respiratory failure (ARF), but knowledge is lacking on the development of endotheliopathy over time in ARF. We, therefore, aimed to evaluate the prognostic significance of trajectories of endotheliopathy during the first days of ARF. We performed a secondary, exploratory analysis of a single-center prospective cohort including 459 patients requiring mechanical ventilation. Based on Days 1-3 Syndecan-1, soluble Thrombomodulin (sTM), and Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), we divided patients into subgroups using latent class mixed modeling and correlated subgroups with clinical outcomes using Cox regression. Based on Syndecan-1 and sTM, respectively, we identified two subgroups. Based on PECAM-1, we identified three subgroups. Subgroups based on Syndecan-1 and sTM were identifiable from the baseline levels, but subgroups based on PECAM-1 were not. Patients with persistently high levels of both sTM and PECAM-1 were liberated from mechanical ventilation more slowly (Group high vs. Group low, sTM: hazard ratio [HR]: 0.66, 95% confidence interval [CI]: 0.50-0.88, p = .01, PECAM-1: HR: 0.59, 95% CI: 0.37-0.93, p = .02) and had higher 30-day mortality (sTM: HR: 1.90, 95% CI: 1.20-3.01, p = .01, PECAM-1: HR: 4.25, 95% CI: 1.99-9.07, p < .01). In ARF requiring mechanical ventilation, patients in subgroups with persistently high levels of sTM and PECAM-1 had lower rates of liberation from mechanical ventilation and higher 30-day mortality. However, patients with persistently high levels of sTM were identifiable based on the baseline level, and only the trajectory of PECAM-1 added information to that of the baseline level.

Quality of life in menopausal women in the workplace - a systematic review.

Menopausal women are a large and economically relevant group in the workforce. Yet their quality of life (QoL) and needs in the workplace have been neglected. Thus, the aim of this systematic review was to provide an overview of QoL of menopausal women in the workplace. Systematic literature searches were executed, yielding 1211 references. After abstract screening, 156 articles remained for full-text screening. Finally, 12 articles fulfilled the inclusion criteria and were included in this review. Age, educational level, type of work, working environment (e.g. crowding, confined spaces, noise, workstation design), permanent place of residency, mental factors (e.g. stress level, workload, work pattern), comorbidities, menopausal symptoms, time since menopause and physical activity have repeatedly been shown to affect QoL in the workplace in menopausal women. Low-threshold access to medical and psychological support as well as individual adaptation of the workplace environment are, among others, retrieved recommendations for employers from these findings. Further raising of awareness of special needs of menopausal working women as well as further systematic research programs are needed.

Goal-directed fluid removal with furosemide versus placebo in intensive care patients with fluid overload: A randomised, blinded trial (GODIF trial-First version).

BACKGROUND: Salt and water accumulation leading to fluid overload is associated with increased mortality in intensive care unit (ICU) patients, but diuretics' effects on patient outcomes are uncertain. In this first version of the GODIF trial, we aimed to assess the effects of goal-directed fluid removal with furosemide versus placebo in adult ICU patients with fluid overload. METHODS: We conducted a multicentre, randomised, stratified, parallel-group, blinded, placebo-controlled trial in clinically stable, adult ICU patients with at least 5% fluid overload. Participants were randomised to furosemide versus placebo infusion aiming at achieving neutral cumulative fluid balance as soon as possible. The primary outcome was the number of days alive and out of the hospital at 90 days. RESULTS: The trial was terminated after the enrolment of 41 of 1000 participants because clinicians had difficulties using cumulative fluid balance as the only estimate of fluid status (32% of participants had their initially registered cumulative fluid balance adjusted and 29% experienced one or more protocol violations). The baseline cumulative fluid balance was 6956 ml in the furosemide group and 6036 ml in the placebo group; on day three, the cumulative fluid balances were 1927 ml and 5139 ml. The median number of days alive and out of hospital at day 90 was 50 days in the furosemide group versus 45 days in the placebo group (mean difference 1 day, 95% CI -19 to 21, p-value .94). CONCLUSIONS: The use of cumulative fluid balance as the only estimate of fluid status appeared too difficult to use in clinical practice. We were unable to provide precise estimates for any outcomes as only 4.1% of the planned sample size was randomised.

Bioimpedance as a measure of fluids in patients with septic shock. A prospective observational study.

BACKGROUND: Septic shock is often treated with aggressive fluid resuscitation leading to profound fluid overload. The assessment of fluid status relies on suboptimal measures making treatment difficult. Bioelectrical impedance analysis is an alternative but the validity is unclear. The aim of this study was to determine the validity of bioelectrical impedance analysis for fluid measures in patients with septic shock. METHODS: Single-center, prospective observational cohort study. We included adult ICU patients with septic shock. We evaluated the agreement between measures on the left and right side of the patient and measures 1 h apart by two bioelectrical impedance devices. Results are presented as Bland Altman plots with 95% Limits of Agreements (LoA) and as correlations between bioelectrical impedance analysis results and clinical markers of fluids. RESULTS: Forty-nine patients were included. The agreement between measures on the left and the right side of the patient and after 1 h was overall without bias, but with wide LoA's. Fluid overload 1 h apart showed the most narrow 95% LoA (-2.4-2.9 L). The same wide limits of agreements were observed when comparing devices. For example, total body water with 95% LoA of -14.8 -16.7 L. Correlations between bioelectrical impedance analysis and clinical measures were low but statistically significant. CONCLUSIONS: In patients with septic shock bioelectrical impedance analysis had no systematic errors or bias, but wide limits of agreement, indicating that the devices have a large and uncorrectable random error. Fluid status by bioelectrical impedance analysis is not sufficiently accurate to guide treatment in this group of patients.

Effects of food matrix on the prebiotic efficacy of inulin-type fructans: a randomised trial.

Recently there is much debate in the scientific community over the impact of the food matrix on prebiotic efficacy of inulin-type fructans. Previous studies suggest that prebiotic selectivity of inulin-type fructans towards bifidobacteria is unaffected by the food matrix. Due to differences in study design, definitive conclusions cannot be drawn from these findings with any degree of certainty. In this randomised trial, we aimed to determine the effects that different food matrices had on the prebiotic efficacy of inulin-type fructans following a standardised 10-day, 4-arm, parallel, randomised protocol with inulin either in pure form or incorporated into shortbread biscuits, milk chocolate or a rice drink. Similar increases in Bifidobacterium counts were documented across all four interventions using both fluorescence in situ hybridisation (pure inulin: +0.63; shortbread: +0.59; milk chocolate: +0.65 and rice drink: +0.71 (log10 cells/g wet faeces) and 16S rRNA sequencing quantitative microbiome profiling data (pure inulin: +1.21 × 109; shortbread: +1.47 × 109; milk chocolate: +8.59 × 108 and rice drink: +1.04 × 109 (cells/g wet faeces) (all P ≤ 0.05). From these results, we can confirm that irrespective of the food matrix, the selectivity of inulin-type fructans towards Bifidobacterium is unaffected, yet the compositional make-up of the food matrix may have implications regarding wider changes in the microbiota.

Goal directed fluid removal with furosemide versus placebo in intensive care patients with fluid overload: A trial protocol for a randomised, blinded trial (GODIF trial).

BACKGROUND: Fluid overload is a risk factor for mortality in intensive care unit (ICU) patients. Administration of loop diuretics is the predominant treatment of fluid overload, but evidence for its benefit is very uncertain when assessed in a systematic review of randomised clinical trials. The GODIF trial will assess the benefits and harms of goal directed fluid removal with furosemide versus placebo in ICU patients with fluid overload. METHODS: An investigator-initiated, international, randomised, stratified, blinded, parallel-group trial allocating 1000 adult ICU patients with fluid overload to infusion of furosemide versus placebo. The goal is to achieve a neutral fluid balance. The primary outcome is days alive and out of hospital 90 days after randomisation. Secondary outcomes are all-cause mortality at day 90 and 1-year after randomisation; days alive at day 90 without life support; number of participants with one or more serious adverse events or reactions; health-related quality of life and cognitive function at 1-year follow-up. A sample size of 1000 participants is required to detect an improvement of 8% in days alive and out of hospital 90 days after randomisation with a power of 90% and a risk of type 1 error of 5%. The conclusion of the trial will be based on the point estimate and 95% confidence interval; dichotomisation will not be used. CLINICALTRIALS: gov identifier: NCT04180397. PERSPECTIVE: The GODIF trial will provide important evidence of possible benefits and harms of fluid removal with furosemide in adult ICU patients with fluid overload.

Endotheliopathy is associated with slower liberation from mechanical ventilation: a cohort study.

BACKGROUND: Endotheliopathy is suggested as pivotal pathophysiology of sepsis and trauma-associated organ failure, but its role in acute respiratory failure is not yet determined. We investigated if endotheliopathy biomarkers at ICU admission are associated with illness severity and clinical outcomes in patients with acute respiratory failure requiring mechanical ventilation. METHODS: We conducted a prospective single-center cohort study including 459 mechanically ventilated adults at ICU admission. Plasma levels of three endotheliopathy biomarkers were measured at ICU admission: Syndecan-1, soluble Thrombomodulin (sTM), and Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1). The primary outcome was the rate of liberation from mechanical ventilation, which is presented together with the rate of the competing risk of death while still on mechanical ventilation. Secondary outcomes were PaO2/FiO2-ratios on admission and on last measurement in patients dying within five days, and 30-day all-cause mortality. The primary outcome and 30-day all-cause mortality were analyzed using Cox regression, controlled for gender, age, chronic obstructive pulmonary disease, septic shock, heart failure, PaO2/FiO2-ratio at admission, respiratory infection, acute kidney injury, and bilirubin. PaO2/FiO2-ratios were analyzed using linear regression, controlled for age, chronic obstructive pulmonary disease, respiratory infection, and shock. RESULTS: Patients with high sTM were liberated from mechanical ventilation at a lower rate (adjusted hazard ratio (HR) 0.71, for an increase from the 25th to the 75th percentile, 95% confidence interval (CI) 0.54-0.93, p = 0.01). Patients with high PECAM-1 were liberated from mechanical ventilation at a lower rate, but only during the first 5 days (adjusted HR 0.72, for an increase from the 25th to the 75th percentile, 95% CI 0.58-0.9, p < 0.01). High levels of Syndecan-1 and PECAM-1 were associated with a higher rate of death while still on mechanical ventilation. sTM and PECAM-1 were negatively associated with PaO2/FiO2-ratio at ICU admission and no biomarker was associated with last measured PaO2/FiO2-ratio. High levels of all biomarkers were associated with higher 30-day all-cause mortality. CONCLUSION: In acute respiratory failure, endotheliopathy biomarkers are associated with lower rates of liberation from mechanical ventilation, hypoxemia at ICU admission, and 30-day all-cause mortality.

The impact of partial-oral endocarditis treatment on anxiety and depression in the POET trial.

BACKGROUND: The Partial-Oral versus Intravenous Antibiotic Treatment of Endocarditis Trial (POET) found that partial-oral outpatient treatment was non-inferior to conventional in-hospital intravenous treatment in patients with left-sided infective endocarditis. We examined the impact of treatment strategy on levels of anxiety and depression. METHODS: Patients completed the Hospital Anxiety and Depression Scale (HADS) at randomization, at antibiotic completion, and after month 3 and month 6. Changes in anxiety and depression (each subdimension 0-21, high scores indicating worse) were calculated using a repeated measure analysis of covariance model with primary assessment after 6 months. Change in score of 1.7 represented a minimal clinical important difference (MCID). RESULTS: Among the 400 patients enrolled in the POET trial, 263 (66%) completed HADS at randomization with reassessment rates of 86-87% at the three subsequent timepoints. Patients in the partial-oral group and the intravenous group had similar improvements after 6 months in levels of anxiety (-1.8 versus -1.6, P = 0.62) and depression (-2.1 versus -1.9, P = 0.63), although patients in the partial-oral group had numerically lower levels of anxiety and depression throughout. An improvement in MCID scores after 6 months was reported by 47% versus 45% (p = 0.80) patients for anxiety and by 51% versus 54% (p = 0.70) for depression. CONCLUSION: Patients with endocarditis receiving partial-oral outpatient treatment reported similar significant improvements in anxiety and depression at 6 months, as compared to conventionally treated, but numerically lower levels throughout. These findings support the usefulness of partial-oral treatment.

Bioimpedance as a measure of fluid status in critically ill patients: A systematic review.

OBJECTIVE: Precise measurements of fluid status lack valid methods. Bioimpedance is an attractive diagnostic tool because it is noninvasive, quick, and relatively cheap. This systematic review aims to assess the existing evidence of bioimpedance as an accurate measure of fluid status in critically ill patients. DATA SOURCES: PubMed and Embase up till March 2021 were systematically searched (PROSPERO: CRD42020157436). STUDY SELECTION: Eligibility criteria were studies reporting original data from cohorts of adult patients in intensive care units and doing at least one whole-body bioimpedance and one reference test. In addition, studies assessing internal reproducibility were included. DATA EXTRACTION: An extraction form was designed for the purpose. DATA SYNTHESIS: Nine hundred five studies were screened for eligibility, and 28 studies, comprising 1482 individual patients, were included in the final analysis. Eight studies compared bioimpedance with a gold standard, and two of those reported the results adequate. We found a low mean difference, but the 95% limits of agreements had wide limits. The remaining studies applied different surrogates as reference tests. Correlations ranged from 0.05 to 0.99. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) certainty of evidence for all outcomes was very low. CONCLUSIONS: The accuracy of bioimpedance as a measure for fluids in critically ill patients in the intensive care unit cannot be determined. Due to the lack of a gold standard, numerous studies compared bioimpedance with surrogate outcomes with great variability in both designs and results. Assessing the internal reproducibility of bioimpedance had the same limitations, but the studies overall reported good internal reproducibility.

Phrenic nerve block on severe post-hepatectomy shoulder pain: A randomized, double-blind, placebo-controlled, pilot study.

BACKGROUND: Severe shoulder pain occurs frequently after surgery close to the diaphragm, potentially caused by referred pain via the ipsilateral phrenic nerve. We aimed to assess the analgesic effect of an ultrasound-guided phrenic nerve block on moderate to severe right-sided shoulder pain after open partial hepatectomy. METHODS: This was a randomized, double-blind, placebo-controlled, pilot study, comparing ultrasound-guided phrenic nerve block (ropivacaine 0.75 mg/mL) versus placebo (isotonic sodium chloride 0.9 mg/mL) on severe post-hepatectomy shoulder pain (NRS ≥6). Pre- and postoperative spirometry and arterial blood gas analyses were used to assess respiratory function. Subjects with chronic lung disease were excluded. Unfortunately, due to lack of funding, the trial was ended prematurely and therefore presented as a pilot study. RESULTS: One hundred and one subjects were screened for eligibility; 14 subjects were randomized, and two subjects were later excluded; thus, 12 subjects were analyzed with six in each group. A statistically significant difference in reduction in median pain intensity between groups was observed 15 minutes after phrenic nerve block ("ropivacaine first" ΔNRS: -6.0 [-6.0 to -3.0] vs. "saline first" ΔNRS: 0 [-6.0 to 1.0], P = .026). Spirometry results and arterial blood gas analyses were not clinically impacted by the block. CONCLUSIONS: Postoperative phrenic nerve block significantly reduced severe post-hepatectomy shoulder pain. Larger studies are warranted to confirm the lack of clinically relevant block-related impairment of respiratory function.

ABO blood types and sepsis mortality.

BACKGROUND: We aimed to determine if the ABO blood types carry different risks of 30-day mortality, acute kidney injury (AKI), and endothelial damage in critically ill patients with sepsis. This was a retrospective cohort study of three independent cohorts of critically ill patients from the United States and Scandinavia consisting of adults with septic shock. We compared the 30-day mortality across the blood types within each cohort and pooled the results in a meta-analysis. We also estimated the incidence of AKI and degree of endothelial damage, as measured by blood concentrations of soluble thrombomodulin and syndecan-1. RESULTS: We included 12,342 patients with severe sepsis. In a pooled analysis blood type B carried a slightly lower risk of 30-day all-cause mortality compared to non-blood type B (adjusted HR 0.88; 95%-CI 0.79-0.98; p = 0.02). There was no difference in the risk of AKI. Soluble thrombomodulin and syndecan-1 concentrations were lower in patients with blood type B and O compared to blood type A, suggesting less endothelial damage. CONCLUSION: Septic patients with blood type B had less endothelial damage, and a small reduction in mortality. The exposure is, however, unmodifiable.

Short chain fatty acids in human gut and metabolic health.

Evidence is accumulating that short chain fatty acids (SCFA) play an important role in the maintenance of gut and metabolic health. The SCFA acetate, propionate and butyrate are produced from the microbial fermentation of indigestible carbohydrates and appear to be key mediators of the beneficial effects elicited by the gut microbiome. Microbial SCFA production is essential for gut integrity by regulating the luminal pH, mucus production, providing fuel for epithelial cells and effects on mucosal immune function. SCFA also directly modulate host metabolic health through a range of tissue-specific mechanisms related to appetite regulation, energy expenditure, glucose homeostasis and immunomodulation. Therefore, an increased microbial SCFA production can be considered as a health benefit, but data are mainly based on animal studies, whereas well-controlled human studies are limited. In this review an expert group by ILSI Europe's Prebiotics Task Force discussed the current scientific knowledge on SCFA to consider the relationship between SCFA and gut and metabolic health with a particular focus on human evidence. Overall, the available mechanistic data and limited human data on the metabolic consequences of elevated gut-derived SCFA production strongly suggest that increasing SCFA production could be a valuable strategy in the preventing gastro-intestinal dysfunction, obesity and type 2 diabetes mellitus. Nevertheless, there is an urgent need for well controlled longer term human SCFA intervention studies, including measurement of SCFA fluxes and kinetics, the heterogeneity in response based on metabolic phenotype, the type of dietary fibre and fermentation site in fibre intervention studies and the control for factors that could shape the microbiome like diet, physical activity and use of medication.

Developments in understanding and applying prebiotics in research and practice-an ISAPP conference paper.

AIMS: The concept of using specific dietary components to selectively modulate the gut microbiota to confer a health benefit, defined as prebiotics, originated in 1995. In 2018, a group of scientists met at the International Scientific Association for Probiotics and Prebiotics annual meeting in Singapore to discuss advances in the prebiotic field, focussing on issues affecting functionality, research methodology and geographical differences. METHODS AND RESULTS: The discussion ranged from examining scientific literature supporting the efficacy of established prebiotics, to the prospects for establishing health benefits associated with novel compounds, isolated from different sources. CONCLUSIONS: While many promising candidate prebiotics from across the globe have been highlighted in preliminary research, there are a limited number with both demonstrated mechanism of action and defined health benefits as required to meet the prebiotic definition. Prebiotics are part of a food industry with increasing market sales, yet there are great disparities in regulations in different countries. Identification and commercialization of new prebiotics with unique health benefits means that regulation must improve and remain up-to-date so as not to risk stifling research with potential health benefits for humans and other animals. SIGNIFICANCE AND IMPACT OF STUDY: This summary of the workshop discussions indicates potential avenues for expanding the range of prebiotic substrates, delivery methods to enhance health benefits for the end consumer and guidance to better elucidate their activities in human studies.

Biomarker-assisted identification of sepsis-related acute liver impairment: a frequent and deadly condition in critically ill patients.

Background The prognostic impact of mild/moderate liver impairment among critically ill patients is not known. We aimed to determine whether acute liver impairment, as measured by several biomarkers, (i) is frequent, (ii) influences prognosis and (iii) to determine whether such an effect is specific for infected critically ill patients. Methods A biomarker and clinical cohort study based on a randomized controlled trial. All-cause mortality was the primary endpoint. Biomarkers hyaluronic acid (HA), bilirubin, albumin, alkaline phosphatase and the international normalized ratio (INR) were determined. Multivariable statistics were applied to estimate risk increase according to liver biomarker increase at baseline and the model was adjusted for age, APACHE II, severe sepsis/septic shock vs. milder infection, chronic alcohol abuse Charlson's co-morbidity index, cancer disease, surgical or medical patient, body mass index, sex, estimated glomerular filtration rate, mechanical ventilation and the other biomarkers. Time-to-event graphs were used. The patients were critically ill patients (n = 1096) from nine mixed medical/surgical intensive care units without known hepatobiliary disease. Results HA levels differed between infected patients (median 210.8 ng/mL [IQR: 93.2-556.6]) vs. the non-infected (median 56.8 ng/mL [IQR: 31.9-116.8], p < 0.001). Serum HA quartiles 2, 3 and 4 were independent predictors of 90-day all-cause mortality for the entire population (infected and non-infected). However, the signal was driven by the infected patients (positive interaction test, no signal in non-infected patients). Among infected patients, HA quartiles corresponded directly to the 90-day risk of dying: 1st quartile: 57/192 = 29.7%, 2nd quartile: 84/194 = 43.3%, 3rd quartile: 90/193 = 46.6%, 4th quartile: 101/192 = 52.3 %, p for trend: <0.0001. This finding was confirmed in adjusted analyses: hazard ratio vs. 1st quartile: 2nd quartile: 1.3 [0.9-1.8], p = 0.14, 3rd quartile: 1.5 [1.1-2.2], p = 0.02, 4th quartile: 1.9 [1.3-2.6], p < 0.0001). High bilirubin was also an independent predictor of mortality. Conclusions Among infected critically ill patients, subtle liver impairment, (elevated HA and bilirubin), was associated with a progressive and highly increased risk of death for the patient; this was robust to adjustment for other predictors of mortality. HA can identify patients at high risk.

Prebiotic supplementation over a cold season and during antibiotic treatment specifically modulates the gut microbiota composition of 3-6 year-old children.

Supplementing kindergarten children during a cold season with a prebiotic inulin-type fructans product with shorter and longer fructan chains has been shown to reduce febrile episodes requiring medical attention and to lower the incidence of sinusitis. These beneficial effects may be connected to the specific modulation of children's gut microbiota. By applying quantitative and qualitative microbiota analysis this study aimed at characterising the gut microbiota composition and at exploring effects of prebiotic intervention on the gut microbiota during a 24-weeks intervention and during antibiotic treatment in healthy children. The study was a randomised, placebo-controlled trial with 258 healthy children aged 3 to 6 years consuming 6 g/day prebiotic inulin-type fructans or maltodextrin. During the course of the study, faecal samples were collected and subject to targeted qPCR analysis and phylogenetic profiling by multiplexed high throughput sequencing of the prokaryotic 16S rRNA gene PCR amplicons. The microbiota composition of the cohort could be clustered into three distinct constellations (enterotypes). Prebiotic intake resulted in a selective modulation of the gut microbiota composition. Relative abundance of Bifidobacterium was significantly higher in the prebiotic group (n=104) compared to control group (n=105) and this effect was found for all three enterotypes. Antibiotic administration decreased the relative abundance of Bifidobacterium in both groups. Nonetheless, children of the prebiotic group receiving antibiotic treatment displayed significantly higher levels of Bifidobacterium than children receiving the placebo control. Prebiotic supplementation induced specific changes in the gut microbiota composition of children aged 3 to 6 years. Moreover, it attenuated antibiotic-induced disturbances in the gut microbiota composition as shown by higher relative abundance of bifidobacteria at the end of the antibiotic treatment in the prebiotic group. With the previously reported benefits on immune function, the study contributes to the evidence on the immune-modulating effects of prebiotics through gut microbiota modifications. The study was registered as NCT03241355 ( https://clinicaltrials.gov/show/NCT03241355 ).

Predicting recovery from acute kidney injury in critically ill patients: development and validation of a prediction model.

OBJECTIVE: Intensive care unit (ICU) patients with acute kidney injury (AKI) who recover kidney function within 28 days experience less severe chronic kidney impairment and have increased long term survival. The aims of this study were to develop and validate a risk prediction model to identify these patients. DESIGN: Observational study with development and validation of a risk prediction model. SETTING: Nine academic ICUs in Denmark. PARTICIPANTS: Development cohort of critically ill patients with AKI at ICU admission from the Procalcitonin and Survival Study cohort (n = 568), validation cohort of adult patients with AKI admitted to two university hospitals in Denmark in 2012-13 (n = 766). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Recovery of kidney function was defined as living for 5 consecutive days with no renal replacement therapy and with creatinine plasma levels below 1.5-fold the levels determined before ICU admission. RESULTS: A total of 266 patients (46.8%) recovered prior kidney function in the development cohort, and 453 patients (59.1%) in the validation cohort. The prediction model included elevation in creatinine, urinary output, sex and age. In the validation cohort, 69 patients (9.0%) had a predicted chance of recovery < 25%, and their observed rate of recovery was 21.5%. This observed rate of recovery was 81.7% among the 325 patients who had a predicted chance > 75%. The area under the receiver operations curves for predicting recovery in the validation cohort was 73.1%. CONCLUSION: We constructed and validated a simple model that can predict the chance of recovery from AKI in critically ill patients.

Duration of acute kidney injury in critically ill patients.

BACKGROUND: Duration of acute kidney injury (AKI) has been recognized a risk factor for adverse outcomes following AKI. We sought to examine the relationship of AKI duration and recurrent AKI with short-term outcomes in critically ill patients who were mechanically ventilated and met criteria for the acute respiratory distress syndrome. METHODS: Participants in the NHLBI ARDS Network SAILS multicenter trial who developed AKI were included in this analysis and divided into groups based on AKI duration. Differences in outcomes were evaluated using t test and Chi-square test. Competing risks regression and Cox regression were used to evaluate factors associated with resolving AKI and recurrent AKI. RESULTS: In total, 238 patients were included in the study. Seventy-seven patients had short duration AKI (1-2 days), 47 medium duration AKI (3-7 days), 87 persistent AKI (> 7 days) and 38 died during their AKI episode. Persistent AKI was associated with worse outcomes including increased ICU length of stay, time on the ventilator and days with cardiovascular failure. We found no clinical differences between patients with short and medium duration AKI, even when accounting for AKI severity and recurrent AKI. Patients with resolving AKI were less likely to have oliguria or moderate/severe ARDS on the day AKI criteria were met. Recurrent AKI was associated with poorer clinical outcomes. No baseline clinical factors were found to predict development of recurrent AKI. CONCLUSIONS: In critically ill patients with sepsis-associated ARDS and AKI, the impact of short and medium duration AKI on clinical outcomes was modest. Persistent and recurrent AKI were both associated with worse clinical outcomes, emphasizing the importance of identifying these patients, who may benefit from novel interventions.